Viruses cause approximately 15% of human cancers. A viral etiology to a human cancer can have substantive consequences on its treatment and prevention. For example, many virally-caused human cancers express virally encoded products, which are potential targets for anti-viral, tumor-specific therapies. In addition unique sets of cellular genes and pathways contribute to virally-associated cancers, many of which are currently being pursued as targets for anti-cancer therapies. This program project grant (PPG), now In its 35th year of continual funding, has two objectives: to use molecular biology and genetics to elucidate the life cycles of and transformation by human tumor viruses and to translate this understanding into the identification of targets for specific anti-viral, ant-tumor therapies. The PPG has seven senior investigators who share these research goals in studying human tumor viruses in three different virus families: papillomaviruses, hepadnaviruses and herpesviruses. Together, these three families of viruses cause the vast majority of virally-associated human cancers. Our PPG evolved over the current funding period to be composed of projects in which two or more investigators work together on a common theme in human tumor virology. Cross-fertilization of ideas and expertise between projects is fostered by having investigators work on multiple projects. This interactive and collaborative organization has been highly fruitful over th current funding period in several regards. Firstly, each project has been highly productive. Secondly, innovative new ideas and approaches have arisen many of which are now being used across multiple projects. Thirdly, the collaborative environment created by this PPG has spawned new interactions that are bringing additional expertise to the PPG. Most important of these interactions have been collaborations between Drs. Shannon Kenney and Rob Kalejta that have led to our including Dr. Kalejta as a new co-leader on two existing projects. The specific themes of this PPG are: 1) to identify and characterize cellular genes that drive human papillomavirus-associated cancer and modulate viral infection; 2) to define the role of the hepatitis B virus core protein in multiple steps of the viral life cycle; 3) to study the replicatin and inheritance of herpesviral genomes in relevant cell types using novel approaches for live cell imaging; 4) to characterize cellular and viral factors that regulate the switch from the laten to lytic viral state of Epstein Barr virus (EBV); and 5) to define drivers of EBV-associated carcinogenesis and develop novel approaches for treating these cancers and diseases caused by herpesviruses.